F7 Drives Gastric Cancer Metastasis Through Anoikis Resistance and Tumor Microenvironment Remodeling

ABSTRACT Coagulation factor VII (F7) has been implicated in tumor progression; however, its role in gastric cancer metastasis and immune evasion remains incompletely understood. In this study, we identified F7 as a clinically relevant driver of gastric cancer. F7 was highly expressed in tumor tissues and closely associated with lymph node metastasis, poor prognosis, and reduced CD8 + T‐cell infiltration. Tumor‐derived autocrine F7 interacted with ITGA2 on the cancer cell surface and activated ITGA2‐associated FAK–NF‐κB signaling and promoted invasion, migration, and anoikis resistance. F7 induced PD‐L1 expression in a manner partly dependent on ITGA2‐mediated PI3K–AKT signaling and promoted collagen I deposition in liver metastatic lesions, which was associated with reduced CD8 + T‐cell infiltration. Co‐immunoprecipitation showed that the K1.2 and K1.3 regions of F7 mediated its interaction with the N‐terminal extracellular region of ITGA2. Further investigations identified HNF4A as an upstream transcription factor of F7, with anoikis‐associated stress enhancing HNF4A nuclear accumulation and F7 transcription. Notably, ThonningianinA (THA) was identified as a potential F7‐targeting small molecule that suppressed F7‐associated malignant phenotypes, reduced tumor growth, and enhanced the antitumor efficacy of anti–PD‐1 therapy. These findings support F7 as a potential therapeutic target for metastatic gastric cancer.